CN108368149A - Method for preventing or treating nosocomial pneumonia - Google Patents
Method for preventing or treating nosocomial pneumonia Download PDFInfo
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- CN108368149A CN108368149A CN201680068970.2A CN201680068970A CN108368149A CN 108368149 A CN108368149 A CN 108368149A CN 201680068970 A CN201680068970 A CN 201680068970A CN 108368149 A CN108368149 A CN 108368149A
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- C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
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- C07K16/46—Hybrid immunoglobulins
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/522—CH1 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/524—CH2 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/526—CH3 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Abstract
It provides a kind of for preventing or treating iatrogenic disease, such as the method by the microbial disease of P. aeruginosa.This method includes the bispecific antibody of specific binding pseudomonas aeruginosa Psl and PcrV that prescribed dose is given to susceptible human experimenter.
Description
Sequence table
The application contains the sequence electronically submitted and be incorporated herein by reference in their entirety with ASCII fromat
Table.The ASCII copy creatings were on November 17th, 2016, entitled PSEUD-200-WO-PCT_SL.txt and size is
22,415 bytes.
Background technology
Pseudomonas aeruginosa (Pseudomonas aeruginosa, P.aeruginosa) is a kind of important iatrogenic disease
Substance, and pneumonia is one of its maximally related form of expression.Mechanical ventilation is to cause Nosocomial pneumonia by pseudomonas aeruginosa
Most important risk factors, with duration of ventilation extension accumulative risk increase (Zahar, JR, et al.Crit Care
Med.2009Sep;37(9):2545-51 [Zahar, JR, et al., critical care medicine magazine, in September, 2009;37(9):2545-
51]).In being studied at one, pseudomonas aeruginosa accounts for micro- life that on-mechanical ventilated patient obtains in intensive care unit (ICU)
The 13% of the pneumonia case that object confirms, and account for 24% (Esperatti et of the pneumonia case in patients with mechanical ventilation
al,Am JRespir CareMed.2010Dec 15;182(12):1533-9 [Esperatti et al., the U.S. breathing with it is critical
Sick medicine, on December 15th, 2010;182(12):1533-9]).In the summary of global epidemiology data, P. aeruginosa
Bacterium causes about 27% Ventilator Associated Pneumonia (VAP;Jones,Clin InfectDis.2010Aug 1;51Suppl
1:S81-7 [Jones, clinical infection's disease, on August 1st, 2010;51 supplementary issues 1:S81-7]).The respiratory tract of pseudomonas aeruginosa is fixed
Plant is another important risk factors (Rehm and Kollef, Poster#367.43rd Critical Care
Congress,Society ofCritical Care Medicine(SCCM);9-13January 2014,San
Francisco CA, USA [Rehm and Kollef, the 43rd critical care medicine meeting poster #367, critical care medicine association of the U.S.
(SCCM);9-13 days in January, 2014, California, USA Los Angeles]).Despite the presence of antibiotic, but since pseudomonas aeruginosa causes
Pneumonia (especially VAP) still with the significant death rate and incidence, increased ICU and hospital stay time and huge
Financial burden is associated.
Patient in ICU is under the risk for developing serious pneumonia, and mechanical ventilation can increase the pneumonia in ICU
Risk.Pseudomonas aeruginosa is the main reason for causing ICU pneumonia, and ICU pneumonia significantly causes the increased hospital stays (55.4
It was relative to 7.2 days), (62.3% is opposite for the mechanical ventilation demand of ICU residence times (14.8 days relative to 1.1 days) and bigger
7.4%) and mortality in (20.2% relative to 3.1%).(Kyaw MH,et al.JInfect Dis.(2005)
192(3):377-386 [Kyaw MH, et al., infectious disease magazine, (2005) 192 (3):377-386]).In addition, multi-drug resistant
The management of charrin disease is set to become complicated.Under limited antimicrobial therapy option, new method is considered, such as
Immunoprophylaxis for preventing pseudomonas aeruginosa will solve an important unsatisfied demand.
MEDI3902 is a kind of 1 (IgG1) κ monoclonal antibodies (mAb) of bivalent, bispecific human immunoglobulin G, this is anti-
PcrV albumen on body selective binding pseudomonas aeruginosa surface and Psl exocellular polysaccharides.Pharmaceutical research is proved
MEDI3902 can mediate three kinds of different mechanism of action:Anti-cell toxicity, opsonophagocytosis and killing, and inhibit verdigris false single
Born of the same parents bacterium is attached to cell.It is combined with the PcrV on complete pseudomonas aeruginosa and 3 types is prevented to secrete (T3S) injecting body
(injectisome) cytotoxicity mediated and the damage to host cell.Being combined with Psl has mediated host effector cell to copper
The opsonophagocytosis of green pseudomonad kills (OPK) and pseudomonas aeruginosa is inhibited to be attached to host epithelial cells
(DiGiandomenico et al,JExp Med.2012Jul 2:209(7):1273-87 [DiGiandomenico et al., it is real
Test medical journal, on July 2nd, 2012:209(7):1273-87]).
MEDI3902 has high protectiveness in pseudomonas aeruginosa Infection in Rodents model.See, for example, PCT Publication WO
2013/070615, PCT Publication WO 2014/074528, PCT Application No. PCT/US 2015/029063 and PCT Application No.
PCT/US 2015/036576.In addition, MEDI3902 is provided for the antibiotherapy of pseudomonas aeruginosa pneumonia and for anti-
The other collaboration enhancing of the different antibiotics of raw element sensibility and antibiotic resistance pseudomonas aeruginosa.
Invention content
The present disclosure provides a kind of prevention or the methods for treating the hospital-acquired infection in susceptible human experimenter, the wherein party
Method includes giving about 500 to about 3000mg to the subject, for example, about 500,600,700,750,1000,1500 or about 3000mg
Specific binding pseudomonas aeruginosa Psl and PcrV bispecific antibody (such as MEDI3902), and from giving the same day
The symptom of the subject is monitored in 21 days started.According to this method, 21 days after giving, which can be asymptomatic
Or it can show the smaller symptom of seriousness relative to the group for the susceptible human experimenter for giving placebo.In some aspects
In, hospital-acquired infection can be pneumonia (such as pseudomonas aeruginosa pneumonia), bacteremia, infection of bone, the infection of joint, skin sense
Dye, infection of burn, wound infection, or any combination thereof.
Present disclosure additionally provides a kind of prevention or treats pneumonia (such as the pseudomonas aeruginosa lung in susceptible human experimenter
It is scorching) method, wherein this method include give about 500 to about 3000mg, for example, about 500 to the subject, 600,700,750,
1000, the specific binding pseudomonas aeruginosa Psl and PcrV of 1500 or about 3000mg bispecific antibody (such as
MEDI3902 the symptoms of pneumonia of the subject), and in 21 days since giving the same day is monitored.According to this method, giving
At least 21 days afterwards, which can be no pneumonia or can be relative to the group for the susceptible human experimenter for giving placebo
Show the smaller symptom of seriousness.
In some embodiments, the serum target level of bispecific antibody (such as MEDI3902) is at least about 1 μ g/
ML, at least about 2 μ g/mL, at least about 3 μ g/mL, at least about 4 μ g/mL or at least about 5 μ g/mL.In other embodiments, double spies
The serum target level of heterogenetic antibody (such as MEDI3902) is at least about 1.7 μ g/mL.In a further embodiment, double special
The serum target level of property antibody (such as MEDI3902) is at least about 5.3 μ g/mL.In some embodiments, double spies are being given
The 21st day after heterogenetic antibody, this, which is given, generated at least 1 μ g/mL, at least about 2 μ g/mL, at least about 3 μ g/mL, at least about 4 μ
The serum levels of the bispecific antibody (such as MEDI3902) of g/mL or at least about 5 μ g/mL.In other embodiments, to
The 21st day after bispecific antibody is given, this gives the bispecific antibody (such as MEDI3902) for generating at least 1.7 μ g/mL
Serum levels.In a further embodiment, the serum target level of bispecific antibody (such as MEDI3902) is at least about
5.3μg/mL
In some embodiments, the method prevented or treat the hospital-acquired infection in susceptible human experimenter is double including giving
Specific antibody, the bispecific antibody include the binding structural domain of specific binding pseudomonas aeruginosa Psl, the integrated structure
Domain includes one group of complementary determining region (CDR):HCDR1-Psl, HCDR2-Psl, HCDR3-Psl, LCDR1-Psl, LCDR2-Psl with
And LCDR3-Psl, wherein HCDR1-Psl have amino acid sequence SEQ ID NO:10, HCDR2-Psl have amino acid sequence
SEQ ID NO:11, HCDR3-Psl have amino acid sequence SEQ ID NO:12, LCDR1-Psl have amino acid sequence SEQ
ID NO:13, LCDR2-Psl have amino acid sequence SEQ ID NO:14, and LCDR3-Psl has amino acid sequence SEQ
ID NO:15;And the binding structural domain of specific binding pseudomonas aeruginosa PcrV, the binding structural domain include one group of CDR:
HCDR1-PcrV, HCDR2-PcrV, HCDR3-PcrV, LCDR1-PcrV, LCDR2-PcrV and LCDR3-PcrV, wherein
HCDR1-PcrV has amino acid sequence SEQ ID NO:2, HCDR2-PcrV have amino acid sequence SEQ ID NO:3,
HCDR3-PcrV has amino acid sequence SEQ ID NO:4, LCDR1-PcrV have amino acid sequence SEQ ID NO:6,
LCDR2-PcrV has amino acid sequence SEQ ID NO:7, and LCDR3-PcrV has amino acid sequence SEQ ID NO:8.
In certain aspects, bispecific antibody has heavy chain and light chain.The heavy chain includes Formula V H-CH1-H1-L1-S-L2-H2-CH2-
CH3, wherein VH are comprising amino acid sequence SEQ ID NO:1 resisting pseudomonas aeruginosa PcrV heavy-chain variable domains, CH1 are
Heavy-chain constant domains -1, H1 are the first heavy chain hinge region segments, and L1 is the first connector, and S is comprising amino acid sequence SEQ
ID NO:9 resisting pseudomonas aeruginosa Psl ScFv molecules, L2 are the second connectors, and H2 is the second heavy chain hinge region segment, and CH2 is
Heavy-chain constant domains -2, and CH3 is heavy-chain constant domains -3.The light chain includes Formula V L-CL, and wherein VL is to include
Amino acid sequence SEQ ID NO:5 resisting pseudomonas aeruginosa PcrV light variable domains, and CL includes antibody light chain κ permanent
Determine area or the areas antibody light chain λ.In certain aspects, CH1 can include amino acid sequence SEQ ID NO:16.In some aspects
In, L1 and L2 can be same or different, and can include independently (a) [GGGGS] n, wherein n be 0,1,2,3,4
Or 5 (SEQ ID NO:23);(b) [GGGG] n, wherein n are 0,1,2,3,4 or 5 (SEQ ID NO:24);Or (a) and (b)
Combination.In certain aspects, H1 can include amino acid sequence EPKSC (SEQ ID NO:17).In certain aspects, H2 can be with
Including amino acid sequence DKTHTCPPCP (SEQ ID NO:18).In certain aspects, CH2-CH3 can include amino acid sequence
SEQ ID NO:19.In certain aspects, CH2-CH3 can include amino acid sequence SEQ ID NO:20.In certain aspects,
The heavy chain of bispecific antibody can include amino acid sequence SEQ ID NO:21, and light chain includes amino acid sequence SEQ ID
NO:22。
According to method provided herein, bispecific antibody (such as MEDI3902) can be used as (IV) in single dose intravenous defeated
Note is given.
According to method provided herein, when giving bispecific antibody, subject can be in respiratory tract (breathing under such as
Road) in field planting have pseudomonas aeruginosa.In certain aspects, subject does not have symptoms of pneumonia when giving.In some aspects
In, the previous day for giving the bispecific antibody, two days, three days or four days, the respiratory tract field planting of the subject had verdigris false
Monad.Field planting can be for example by detecting verdigris in before giving the bispecific antibody 36 hours in tracheal aspirate
Pseudomonad measures.In certain aspects, when giving the bispecific antibody, in addition the respiratory tract of the subject can be determined
It is implanted with staphylococcus aureus.
In certain aspects, which will be hospitalized, currently be hospitalized (such as in intensive care unit (ICU)), most
It is close to be hospitalized, using mechanical respirator (such as be intubated or ventilate by tracheal strips or nasotracheal tube).
According to method provided herein, mechanical ventilation is given while the bispecific antibody can reduce mechanical ventilation or no longer needed
Pneumonia risk later.
In certain aspects, the microbiology confirmation of pneumonia may include being positive to pseudomonas aeruginosa by culture
The liquor pleurae that pseudomonas aeruginosa is positive is sucked out in respiratory tract sample, the blood cultures being positive to pseudomonas aeruginosa
Object or lung tissue culture, or any combination thereof.
In certain aspects, which does not receive quilt before giving the bispecific antibody (for example, MEDI3902)
Think the active antibiotic of the pseudomonas aeruginosa strains being colonized for the subject.In in other respects, the party
Method may further include to subject and give antibiotic.In certain aspects, the pseudomonas aeruginosa that subject is colonized
Bacterial strain can be to antibiotic sensitive, or can be to antibiotics resistance or part drug resistance.When giving antibiotic, which can
To be given before giving the bispecific antibody, with give the bispecific antibody and give simultaneously, giving the bispecific
Given after antibody, or any combination thereof.
In certain aspects, this method may further include to subject and give antihistaminic.When giving antihistaminic
When, which can give before giving the bispecific antibody, with give the bispecific antibody give simultaneously, to
Give give after the bispecific antibody, or any combination thereof.
Description of the drawings
Fig. 1 provides the flow chart of IIb clinical trial phase research approaches.The anti-medicine antibody of ADA=;IV=is intravenous;N=by
Examination person's quantity;PK=pharmacokinetics.Curative effect 21 days (the 22nd day) will be evaluated upon administration;Safety, PK and ADA will be
(the 50th day) is evaluated 49 days after administration.Blind evaluation based on incident rate and/or decline rate in total group, sample size
It can modify after the subject for recruiting about 50%, and be tracked within 21 days upon administration.
The increasing of monoclonal antibodies (such as MEDI4893) of the Fig. 2 based on the directed toward bacteria pathogen observed in ICU patient
The clearance rate added, for the pharmacokinetic modeling for the ICU patient for using mechanical ventilation after the MEDI3902 of single dose.
(A) prediction single dose 1500mg MEDI3902 exist>Continue to maintain the serum of about 1 μ g/mL sudden and violent in >=21 days in 90% subject
Dew.(B) prediction single dose 3000mg MEDI3902 exist>Continue to maintain about 1.7 μ g/mL's in >=21 days in 90% subject
Serum exposes.
The internal survival research of the mouse of MEDI3902 processing of the Fig. 3 in 6206 acute pneumonia model systems.With of the same race
Type compares IgG (negative control, 0.75mg/kg) or MEDI3902 with following Three doses processing mouse (n=6):1mg/kg、
0.5mg/kg or 0.2mg/kg.All mouse are used about 2 × 10 by twenty four hours after treatment5The verdigris of CFU/ animals is false single
Born of the same parents' bacteria strain 6206 infects.All mouse are monitored 168 hours.About 120 hours after infection, all control group mices were dead
In infection.The animal of all MEDI3902 processing all survives.As a result Kaplan-Meier (Kaplan-Meier) is expressed as to deposit
Curve living.
Specific implementation mode
Abbreviation
The abbreviation used in present disclosure is listed in Table 1.
Table 1:Abbreviation
Definition
It should be pointed out that term "/kind (a or an) " entity refers to/kind or multiple/kind of entity;For example, " one
Kind binding molecule " is understood to mean that one or more binding molecules.Therefore, term "/kind (a or an) ", "/kind
Or multiple/kind " and " at least one/kind " can be used interchangeably herein.
In addition, when used herein "and/or" be understood to the two specified features or component each with or without
The specific disclosure of another one.Therefore, in use, being intended to include " A in the phrase of term "and/or" such as this paper such as " A and/or B "
And B ", " A or B ", " A " (independent) and " B " (independent).Equally, term "and/or" is such as in phrase such as " A, B and/or C "
Each of following aspect is intended to cover when use:A, B and C;A, B or C;A or C;A or B;B or C;A and C;A and B;B and C;
A (independent);B (independent);And C (independent).
Unless otherwise defined, otherwise technical and scientific term used herein has the general of the field being related to present disclosure
The identical meaning that logical technical staff is generally understood.For example, Concise Dictionary of Biomedicine and
Molecular Biology [concise biomedical and molecular biology dictionary], Juo, Pei-Show, second edition, 2002, CRC go out
Version society;Dictionary of Cell and Molecular Biology [Cytobiology and molecular biology dictionary], the 3rd edition,
1999, Academic Press [academic press];And Oxford Dictionary Of Biochemistry And
Molecular Biology [biochemistry and molecular biology oxford dictionary], revised edition, 2000, Oxford University
Press [Oxford University Press] provides the universaling dictionary annotation of many terms used in present disclosure for technical staff.
Unit, prefix and symbol indicate in the form of their international system of units (SI) receives.Numberical range includes limit
The number of the fixed range.Unless otherwise stated, otherwise amino acid sequence is orientated to carboxyl with amino and writes from left to right.It carries herein
The subhead of confession is not the different aspect of present disclosure or the limitation of various aspects, can be by referring to this specification as a whole
To obtain these aspects.Therefore, it by reference explanation book in its entirety, more fully defines and to be defined immediately below
Term.
It there is disclosed herein certain binding molecules or its antigen-binding fragment, variant or derivative.Unless definitely referring to
Such as naturally occurring antibody of full-scale antibody, otherwise term " binding molecule " cover full-scale antibody and this kind of antibody
Antigen-binding fragment, variant, analog or derivative, such as naturally occurring antibody or immunoglobulin molecules or engineering resist
Body molecule or the segment that antigen is combined in a manner of similar to antibody molecule.
As used herein, term " binding molecule " refers to molecule of the antigen binding determinant on its most broad sense
Molecule.As further described herein, binding molecule may include one or more " binding structural domains ".As used herein, " knot
Close structural domain " it is the two-dimentional or three-dimensional polypeptide structure that can specifically bind given antigenic determinant or epitope.Binding molecule
Non-limiting examples be bispecific antibody or its segment, the bispecific antibody or its segment include that specific binding is different
At least two different binding structural domains of antigenic determinant or epitope.It in certain aspects, it is said that can be with provided in this article
Bispecific antibody includes the first binding structural domain in conjunction with the first epitope and combines the second binding structural domain of the second epitope.
Term " antibody " and " immunoglobulin " can be used interchangeably herein.Antibody (or its piece as herein disclosed
Section, variant or derivative include the variable domains of at least variable domains of heavy chain and at least heavy chain and light chain.Vertebra is dynamic
The basic immunoglobulin structure of object system is relatively sufficiently understood.See, for example, Harlow et al.,
Antibodies:A Laboratory Manual,(Cold Spring Harbor Laboratory Press,2nd
Ed.1988) [Harlow et al., antibody:Laboratory manual, (CSH Press, second edition, 1988)].
As discussed in more detail below, term " immunoglobulin " includes the extensive difference that can be distinguished in biochemistry
The polypeptide of classification.Have it will be understood by those skilled in the art that heavy chain is classified as or ε (γ, μ, α, δ, ε), among them
Subclass (for example, γ 1- γ 4).The property of this chain determines that " classification " of antibody is IgG, IgM, IgA IgG or IgE respectively.Exempt from
Epidemic disease immunoglobulin subclass (isotype) such as IgG1、IgG2、IgG3、IgG4、IgA1Deng fully being characterized, and known assign function
Specialization.The modified forms of each in these classifications and isotype are in the case where considering present disclosure for those skilled in the art
For be easily discernable, and therefore be in present disclosure in the range of.
Light chain is classified as κ or λ (κ, λ).Each heavy chain classification can be combined with κ or lambda light chain.In general, light chain and heavy chain
It is covalently bonded to one another, and when immunoglobulin is generated by hybridoma, B cell or genetically engineered host cell, two
" tail " of heavy chain is partly bonded together by covalent disulfide bonds or non-covalent bond.In heavy chain, amino acid sequence is from Y configurations
The N-terminal of divergent ends extends to the C-terminal of every chain bottom.
Light chain and heavy chain are both divided among the region with structure and function homology.Term " constant " and " can
Become " it is functionally to use.In this respect, it should be understood that light (VL) chain and the again variable domains of both (VH) chain parts determine anti-
Original identification and specificity.On the contrary, the constant domain of light chain (CL) and heavy chain (CH1, CH2 or CH3) assigns important biology
Characteristic, secrete, combined through placenta mobility, the combination of Fc receptors, complement etc..By convention, the number of constant region domain
As they become to increase further from antigen binding site or the amino terminal of antibody.N-terminal part is variable region, and C
End section is constant region;CH3 and CL structural domains actually separately include the carboxyl terminal of heavy chain and light chain.
As indicated above, variable region allows binding molecule to selectively identify the epitope in simultaneously molecule of the antigen binding.
That is, the VL structural domains and VH structural domains of binding molecule (such as antibody) or the subclass of complementary determining region (CDR) are combined to form limit
Determine the variable region of three dimensional antigen binding site.The quaternary binding molecule structure forms the anti-of the end for each arm for being present in Y
Former binding site.More specifically, antigen binding site by VH and VL chains each on three CDR limit.
In naturally occurring antibody, be present in six " complementary determining regions " in each antigen-binding domains or
" CDR " is short, discrete amino acid sequence, these amino acid are particularly positioned to be presented in aqueous environments in antibody
Antigen-binding domains are formed when its 3-d modelling.Remaining amino acid being referred to as in the antigen-binding domains in " frame " area is aobvious
Show compared with variability between small molecule.Framework region largely uses beta sheet conformation, and CDR forms multiple rings, these rings connect simultaneously
And a part for beta sheet structure is formed in some cases.Therefore, framework region works to form holder, which provides logical
The noncovalent interaction for crossing interchain positions CDR with correct orientation.The antigen binding structure formed by the CDR positioned
Domain defines the surface with the epitope complementation on immunoreactivity antigen.This complementary surface promotes antibody and its homologous epitopes
Non-covalent binding.The amino acid for respectively constituting CDR and framework region can be by those of ordinary skill in the art for any given
Heavy chain or light chain variable region easily differentiate, because they have been obtained for accurately defining (referring to " Sequences of
Proteins of Immunological Interest,"Kabat,E.,et al.,U.S.Department ofHealth
And Human Services, (1983) [" concern of albumen matter sequence in immunology " Kabat, E. et al., U.S. sanitary and public affairs
Many service departments, (1983)];And Chothia and Lesk, J.Mol.Biol., 196:901-917 (1987) [Chothia and
Lesk, J. Mol. BioL, 196:901-917 (1987)], these documents are incorporated herein by reference in their entirety).
Antibody or its antigen-binding fragment, variant or derivative include but not limited to monoclonal antibody
(tomonoclonal), human antibodies, humanized antibody or chimeric antibody, scFv (scFv) and multi-specificity antibody (example
Such as bispecific antibody).ScFv molecules be well known in the art and be described in for example United States Patent (USP) 5,892,019 it
In.The immunoglobulin or antibody molecule that present disclosure covers can be any types (such as IgG, IgE, IgM, IgD, IgA, with
And IgY), the immunoglobulin molecules of classification (such as IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass.
" specific binding " generally refers to binding molecule, such as bispecific antibody or its segment, variant or derivative, warp
By antigen-binding domains combination epitope, and this combination need to have between antigen-binding domains and the epitope it is certain mutual
Benefit property.Binding molecule as provided herein can contain two, three, four, or more binding structural domain, these knots
Structural domain is closed to can be same or different and can combine identical epitope or combine two or more different
Epitope.According to this definition, the binding molecule is easier anti-via it compared with combining random, incoherent epitope with binding molecule
Former binding domain is come when combining an epitope, which is considered as " specific binding " epitope.Term " specificity " exists
It is qualitative for combining the relative affinity of certain epitope to carry out to certain binding molecule herein.For example, with binding molecule " B " phase
Than binding molecule " A " can be considered as having higher specificity for given epitope, or be directed to phase with binding molecule " A "
It closes specificity possessed by epitope " D " to compare, binding molecule " A " can be considered with higher specific binding epitope " C ".
Antibody fragment including single-chain antibody can include individually or with the whole or part group of lower structure
One or more variable regions of conjunction:Hinge area, CH1, CH2 and CH3 structural domain.Further include antigen-binding fragment, the antigen binding
Segment also includes any combinations of one or more variable regions and hinge area, CH1, CH2 and CH3 structural domain.It is disclosed herein anti-
Body or its antigen-binding fragment can come from any animal origin, including birds and mammal.Antibody can be the mankind, mouse
Class, donkey, rabbit, goat, cavy, camel, yamma, horse or chicken antibody.As used herein, " mankind " antibody includes having the mankind
The antibody of the amino acid sequence of immunoglobulin, and include the antibody detached from human immunoglobulin library or from for one
Kind or a variety of human immunoglobulin(HIg) transgenosis and do not express endogenous immunoglobulin animal separation antibody, following article and
Such as described in the U.S. Patent number 5,939,598 of Kucherlapati et al..
As used herein, term " chain moiety " includes the amino acid sequence from light chain immunoglobulin.Light chain
Part includes at least one of VL or CL structural domains.
As used herein, term " multi-specificity antibody " or " bispecific antibody " refer in single antibody intramolecular pair
Two or more not synantigen or epitope have specificity binding structural domain antibody.It should be understood that removing standard antibody structure
Except other molecules can be built into tool there are two types of binding specificity.It is to be further understood that antigen can be simultaneously or successively
It is combined with bispecific antibody.Trioma and hybrids tumor are two of the cell line that can secrete bispecific antibody
Example.Bispecific antibody can also be built by recombinant means.(and Heiss,Future Oncol.6:
1387-94(2010)[And Heiss, future tumors 6:1387-94(2010)];Mabry and Snavely,
IDrugs.13:543-9 (2010) [Mabry and Snavely, new pharmacy 13:543-9(2010)]).
As used herein, term " engineered antibody " refers to the varistructure in either or both of heavy chain and light chain
Domain is by least partly replacing one or more CDR from the antibody with known specificity and as necessary by part
Framework region replaces the antibody changed with sequence variation.Although CDR can derive from class identical with the antibody in framework region institute source
Not or the antibody of even sub-class, it is contemplated however that CDR from different classes of antibody and will be preferably derived from from difference
The antibody of species.Wherein one or more " donor " CDR from the non-human antibody with known specificity is transplanted to people
Engineered antibody in class heavy chain or light chain framework region is referred to herein as " humanized antibody ".It may need not be used for from donor
The complete CDR of variable region replaces all CDR so that the antigen binding capacity of a variable domains is transferred to another.And
It is that possible only need to shift those residues necessary to maintaining the activity of target binding site.In view of such as U.S. Patent number
Illustrated explanation, those skilled in the art are complete in 5,585,089,5,693,761,5,693,762 and 6,180,370
It has the ability by carrying out routine experiment or to obtain function engineering by trial and error experiment (trial and error testing)
Or the antibody of humanization.
As used herein, " " treatment (treat/treatment) " refers to therapeutic treatment to term, wherein aiming at
Clinical diagnosis is with removing in the infection such as subject of pneumonia, bacteremia, peritonitis, septicemia and/or abscess or reduces sense
The former bacterium burden of dye." treatment " can also mean the extended survival compared with expected survival when not receiving treatment.It needs to control
Those for the treatment of subject includes having suffered from those of infection, symptom or illness subject and being easy to suffer from symptom or illness
Those subjects or need to be prevented those of symptom or illness subject, such as is susceptible to suffer from bacterium infection (such as P. aeruginosa
Bacterium infect) fire victim or immunosuppressed patient.
As used herein, term " prevention " or " mitigation " refer to preventative (prophylactic) or preventing property
(preventative) measure, wherein aiming at prevention or slowing down (mitigation) undesirable physiological change, infection or illness.Have
Benefit or desirable clinical effectiveness includes but not limited to alleviate symptom, reduction disease degree, stable disease state (not dislike
Change), remove or reduce infector such as pseudomonas aeruginosa in subject's body, postpone or slow down progression of disease, improving or slow
No matter with morbid state and the detectable or undetectable mitigation arrived (no matter partially or completely).
As used herein, term " iatrogenic disease " and " hospital-acquired infection " refer to occur or originating from hospital or other
The disease of health care institution or infection.Hospital-acquired infection is typically to be suffered from hospital or other health care institutions
(contract) infection, and can be caused by infector (such as to the drug resistant bacterium of antibiotic).In certain aspects, it cures
Source sexuality dye is not present or hides before subject enters hospital or health care institution, is to enter hospital or doctor in subject
Treat what health institution obtained or suffered from later.
Similarly, " iatrogenic illness " or " doctor pathogenic infection " is because medical treatment and nursing causes or the disease occurred or sense
Dye.
" subject " or " individual " or " animal " or " patient " or " mammal " mean to wish diagnosis, prognosis or treatment
Any subject, such as mammalian subject.Mammalian subject includes the mankind, domestic animal, farming animals and zoo, body
It educates or pet animals, dog, cat, cavy, rabbit, rat, mouse, horse, ox, milk cow, bear etc..
As used herein, phrase such as " can benefit from resisting pseudomonas aeruginosa Psl and PcrV bi-specific binding molecule
The subject given " and " animal in need for the treatment of " include can benefit from resisting pseudomonas aeruginosa Psl and PcrV it is bis- specifically
The subject of property binding molecule (such as bispecific antibody) given, such as mammalian subject.This kind of binding molecule can
For for example to pseudomonad Psl or the PcrV detection (such as diagnostic program) carried out and/or for treating, that is, using anti-
Pseudomonas aeruginosa Psl and PcrV bi-specific binding molecule mitigates or prevents disease.As described in more detail, anti-copper
Green pseudomonad Psl and PcrV bi-specific binding molecules can use in the form of unconjugated or can be conjugated to such as medicine
Object, prodrug or isotope.
As used herein, term " susceptible subject " or " susceptible human experimenter " refer to the damage due to being previously or is currently being
Wound or disease, in the works, it is current or previous be hospitalized (such as in intensive care unit), assisted respiartion (such as via
Pass through the mechanical ventilation of intubation or tracheostoma), and/or pseudomonas aeruginosa (wherein pseudomonas aeruginosa in some cases
Can be antibiotics resistance) known field planting in such as respiratory tract, and in disease (such as with pseudomonas aeruginosa
Relevant disease) risk (such as low-risk, medium risk or high risk) in subject, such as human patients.Certain
In aspect, it can be asymptomatic that field planting, which has the subject of pseudomonas aeruginosa, or can show slight, moderate or severe
Disease symptoms, such as symptoms of pneumonia described elsewhere herein.The infection being previously or is currently being can be such as infection of burn, close
Section infection, wound infection, skin infection, intraperitoneal infection, bacteremia, peritonitis, septicemia, abscess, infection of bone or two kinds
Or more this para-infectious combination.In certain aspects, subject can suffer from following infection or in suffering from following sense
Under the risk of dye:Acute pneumonia, burn, corneal infection, cystic fibrosis or combinations thereof.In certain aspects, the susceptible mankind by
Examination person can with bispecific antibody provided herein treat with prevent disease (such as iatrogenic disease, iatrogenic illness or by
The microbial disease of P. aeruginosa) generation, or for example alleviate, reduce, reduce, weaken, weaken, mitigate, cut to mitigate
Weak, mitigation releases the disease caused by charrin disease or infection symptoms, or to treat by pseudomonas aeruginosa
The bacterium burden of charrin disease is for example eliminated or is reduced in caused infection.In certain aspects, susceptible human subjects
Person be for example based on suffer from by the risk factors (as described above) of the medicable disease of method provided herein or since it is desired that
Treatment existing symptom and subject in need for the treatment of.
Bispecific antibody
The method that present disclosure provides be utilized specific binding pseudomonas aeruginosa Psl and PcrV bispecific antibody or
Its antigen-binding fragment.Bispecific antibody disclosed here or its segment include polypeptide, such as are encoded for example from immune
The Psl specificity of globulin molecule and/or the amino acid sequence of the antigen-specific binding regions PcrV." deriving from " specifies protein
Polypeptide or amino acid sequence refer to polypeptide source.In some cases, specific starting polypeptide or amino acid sequence are derived from
Polypeptide or amino acid sequence have amino acid sequence substantially consistent with homing sequence or part of it, wherein the part by
At least 10-20 amino acid, at least 20-30 amino acid, at least 30-50 amino acid composition or the amino acid sequence can
Otherwise differentiated as originating from homing sequence by those of ordinary skill in the art.
It is disclosed in such as PCT Publication WO 2013/ for the Exemplary bispecific antibodies in method provided herein
070615, PCT Publication WO2014/074528, PCT Application No. PCT/US2015/029063 and PCT Application No. PCT/
The disclosure content of US2015/036576, these patents are incorporated herein by reference in their entirety.
Sample portion for the bispecific antibody in method provided herein is presented in table 2.VH, VL and scFv
CDR in sequence is underlined.Joint sequence is added double underline.
Table 2:Sequence
Need according to the bispecific antibody that method in this is given to include the knot for specifically binding pseudomonas aeruginosa Psl
Structural domain is closed, which includes one group of complementary determining region (CDR):HCDR1-Psl、HCDR2-Psl、HCDR3-Psl、
LCDR1-Psl, LCDR2-Psl and LCDR3-Psl, wherein HCDR1-Psl have amino acid sequence SEQ ID NO:10,
HCDR2-Psl has amino acid sequence SEQ ID NO:11, HCDR3-Psl have amino acid sequence SEQ ID NO:12,
LCDR1-Psl has amino acid sequence SEQ ID NO:13, LCDR2-Psl have amino acid sequence SEQ ID NO:14, and
LCDR3-Psl has amino acid sequence SEQ ID NO:15;And the integrated structure of specific binding pseudomonas aeruginosa PcrV
Domain, the binding structural domain include one group of CDR:HCDR1-PcrV、HCDR2-PcrV、HCDR3-PcrV、LCDR1-PcrV、LCDR2-
PcrV and LCDR3-PcrV, wherein HCDR1-PcrV have amino acid sequence SEQ ID NO:2, HCDR2-PcrV have amino
Acid sequence SEQ ID NO:3, HCDR3-PcrV have amino acid sequence SEQ ID NO:4, LCDR1-PcrV have amino acid sequence
Arrange SEQ ID NO:6, LCDR2-PcrV have amino acid sequence SEQ ID NO:7, and LCDR3-PcrV has amino acid sequence
Arrange SEQ ID NO:8.In embodiment, bispecific antibody has heavy chain and light chain.Heavy chain includes Formula V H-CH1-H1-L1-S-
L2-H2-CH2-CH3, wherein VH are comprising amino acid sequence SEQ ID NO:1 resisting pseudomonas aeruginosa PcrV weight chain variable knots
Structure domain, wherein CH1 are that heavy-chain constant domains -1, H1 are the first heavy chain hinge region segments, and L1 is the first connector, and S is to include
Amino acid sequence SEQ ID NO:9 resisting pseudomonas aeruginosa Psl ScFv molecules, L2 are the second connectors, and H2 is the second heavy chain hinge
Sequence segment, CH2 is heavy-chain constant domains -2, and CH3 is heavy-chain constant domains -3.Light chain includes Formula V L-CL,
Wherein VL is comprising amino acid sequence SEQ ID NO:5 resisting pseudomonas aeruginosa PcrV light variable domains, and CL packets
The constant regions of κ containing antibody light chain or the areas antibody light chain λ.In certain aspects, CH1 can include amino acid sequence SEQ ID NO:
16.In certain aspects, L1 and L2 can be same or different, and can include independently (a) [GGGGS] n, wherein
N is 0,1,2,3,4 or 5 (SEQ ID NO:23);(b) [GGGG] n, wherein n are 0,1,2,3,4 or 5 (SEQ ID NO:24);Or
The combination of person (a) and (b).In certain aspects, H1 can include amino acid sequence EPKSC (SEQ ID NO:17).Certain
In aspect, H2 can include amino acid sequence DKTHTCPPCP (SEQ ID NO:18).In certain aspects, CH2-CH3 can be with
Including amino acid sequence SEQ ID NO:19.In certain aspects, CH2-CH3 can include amino acid sequence SEQ ID NO:
20.In certain aspects, the heavy chain of bispecific antibody can include amino acid sequence SEQ ID NO:21, and light chain includes
Amino acid sequence SEQ ID NO:22.
Include the pharmaceutical composition of resisting pseudomonas aeruginosa Psl and PcrV bi-specific binding molecule
Include pharmaceutically acceptable load well known within the skill of those ordinarily skilled for the pharmaceutical composition in present disclosure
Body.The preparation given for parenteral includes sterile aqueous or non-aqueous solution, suspension and lotion.
It can be combined to generate resisting pseudomonas aeruginosa Psl and/or the PcrV bispecific of single formulation with carrier material
Antibody or its segment, the amount of variant or derivative according to the subject treated and specific will be given pattern and changed.It is exemplary
Dosage includes infusion about 500 to about 3000mg in single dose intravenous, for example, about 500mg, 600,700,750,1000,1500 or
Resisting pseudomonas aeruginosa Psl and the PcrV bispecific antibody of about 3000mg.It is best to provide that dosage can also be adjusted
Desirable response (for example, preventative response or therapeutic treatment response).
Resisting pseudomonas aeruginosa Psl and PcrV bispecific antibody or its segment, the approach of giving of variant or derivative can
To be such as parenteral.As used herein, term parenteral include in for example intravenous, intra-arterial, peritonaeum, intramuscular or subcutaneous
It gives.Suitable administration form will be injection solution, especially be used for intravenous or intra-arterial injection or instillation solution.
Resisting pseudomonas aeruginosa Psl and PcrV bispecific antibody or its segment, variant or derivative can be effective with pharmacy
Amount is given for interior therapeutic or prevents charrin disease.In this respect, it should be understood that disclosed knot can be prepared
Molecule is closed to help to give and promote the stability of activating agent.
It is consistent with the range of present disclosure, resisting pseudomonas aeruginosa Psl and PcrV bispecific antibody or its segment, variant or
Derivative can give the mankind or other animals according to above-mentioned therapy with the amount for being enough to generate therapeutic effect.It is disclosed here
Resisting pseudomonas aeruginosa Psl and PcrV bispecific antibody or its segment, variant or derivative can give this person with regular dosage form
Class or other animals, the dosage form be according to known technology by by acceptable carrier in the antibody of present disclosure and conventional pharmaceutical or
Diluent combines to prepare.
The effective dose of the composition of present disclosure for treating charrin disease according to many different factors and
Variation, these factors include mode of giving, target site, patient physiological condition, patient be the mankind or animal, it is to be administered its
His medicament and treatment are preventative or therapeutic.In general, patient is the mankind, but non-human lactation can also be treated
Animal, including transgene mammal.Conventional method titration treatment dosage well known by persons skilled in the art can be used with excellent
Change safety and effect.
According to different factors well known by persons skilled in the art, resisting pseudomonas aeruginosa Psl and PcrV bispecific antibody
Or its segment, variant or derivative can be given using different frequency (such as single dose) in several cases.
Method for preventing or treating Nosocomial pneumonia
The present disclosure provides a kind of method for preventing the hospital-acquired infection in susceptible human experimenter, wherein this method includes
Give about 500mg to about 3000mg to the subject, for example, 500mg, 600mg, 700mg, 750mg, 1000mg, 1500mg or
The bispecific antibody of specific binding the pseudomonas aeruginosa Psl and PcrV of 3000mg dosage.Bispecific antibody can example
Such as about 500mg to the list of about 3000mg, such as 500mg, 600mg, 700mg, 750mg, 1000mg, 1500mg or 3000mg
Secondary dosage is given.In certain aspects, bispecific antibody can be given as IV infusions.As elsewhere herein is more detailed
It carefully describes, susceptible human experimenter is that do not have under the risk for suffering from hospital-acquired infection but when giving infection or do not have
Show the people of infection symptoms;Or suffer from the people for needing intervention or the hospital-acquired infection slowed down.This method further comprise to
Give bispecific antibody monitoring subject in such as 1 day, 3 days, 5 days, 7 days, 10 days, 15 days, 21 days, 28 days or 30 days later
Symptom.In one embodiment, this method includes at least about 21 days or longer time interior monitoring subject from giving the same day
Symptom." hospital-acquired infection " elsewhere herein defines and includes such as pneumonia, bacteremia, infection of bone, the infection of joint, skin
Infection, infection of burn, wound infection, peritonitis, septicemia and/or abscess.It is associated with hospital-acquired infection (such as pneumonia)
Symptom is as known in the art, and in the example that is described below of exemplary symptom.In certain aspects, hospital-acquired infection
Caused by pseudomonas aeruginosa or is aggravated.According to the method, if 1 day for example after giving, 3 days, 5 days, 8 days, 10 days, 15
It, 21 days, 28 days or 30 days, subject keeps asymptomatic (if subject is asymptomatic when giving) or the symptom that shows
Serious expected symptom when being treated not as good as unused MEDI3902, then human experimenter is by successful treatment.In one embodiment
In, if 21 days after giving, subject's holding asymptomatic (if subject is asymptomatic when giving) or the disease shown
Shape is serious not as good as expected symptom when unused MEDI3902 is treated, then human experimenter is by successful treatment.In another reality
Apply in example, if 28 days or 30 days after giving, subject keep asymptomatic (if subject is asymptomatic when giving) or
The symptom shown is serious not as good as expected symptom when unused MEDI3902 is treated, then human experimenter is by successful treatment.
In another aspect, the present disclosure provides it is a kind of prevention or treat in susceptible human experimenter pneumonia (such as
Nosocomial Pneumonia or non-hospital acquired pneumonia) method, wherein this method includes giving about 500mg to about to subject
3000mg, for example, 500mg, 600mg, 700mg, 750mg, 1000mg, 1500mg or 3000mg dosage specific binding verdigris
The bispecific antibody of pseudomonad Psl and PcrV.Bispecific antibody can be for example as about 500mg to about 3000mg, example
It is given such as the single dose of 500mg, 600mg, 700mg, 750mg, 1000mg, 1500mg or 3000mg.In certain aspects,
Bispecific antibody can be given as IV infusions.In certain aspects, pneumonia is iatrogenic or iatrogenic.As herein
Elsewhere in greater detail, susceptible human experimenter is that do not have under the risk for suffering from pneumonia but when giving pneumonia
The people of symptom;Or suffer from the people for needing intervention or the pneumonia slowed down.This method further comprises giving bispecific antibody
The symptoms of pneumonia of subject is monitored in such as 1 day, 3 days, 5 days, 7 days, 10 days, 15 days, 21 days, 28 days or 30 days later.One
In a embodiment, this method includes the symptom of at least about 21 days monitoring subjects from giving the same day.Disease associated with pneumonia
Shape is known in the art, and in the example that is described below of exemplary symptom.In certain aspects, pneumonia is false single by verdigris
Born of the same parents bacterium causes or aggravates.According to the method, if 1 day, 3 days, 5 days, 8 days, 10 days, 15 days, 21 days, 28 days for example after giving
Or 30 days, subject keeps asymptomatic (if subject is asymptomatic when giving) or the symptom shown not as good as unused
Expected symptom is serious like that when MEDI3902 is treated, then human experimenter is by successful treatment.In one embodiment, if
7 days after giving, subject keeps asymptomatic (if subject is asymptomatic when giving) or the symptom shown not as good as unused
Expected symptom is serious like that when MEDI3902 is treated, then human experimenter is by successful treatment.In one embodiment, if
21 days after giving, subject keeps asymptomatic (if subject is asymptomatic when giving) or the symptom shown not as good as unused
Expected symptom is serious like that when MEDI3902 is treated, then human experimenter is by successful treatment.In another embodiment, if
28 days or 30 days after giving, subject's holding asymptomatic (if subject is asymptomatic when giving) or the symptom shown
Serious expected symptom when being treated not as good as unused MEDI3902, then human experimenter is by successful treatment.
In another aspect, the present disclosure provides it is a kind of prevention or treat in susceptible human experimenter by P. aeruginosa
Microbial disease for example pneumonia, tracheobronchitis, bacteremia, endocarditis, meningitis, tympanitis, bacterial keratitis,
Entophthamia, osteomyelitis, gastrointestinal disease, skin infection, septicemia or any combination thereof method, wherein this method includes to tested
Person gives about 500mg to about 3000mg, such as 500mg, 600mg, 700mg, 750mg, 1000mg, 1500mg or 3000mg dosage
Specific binding pseudomonas aeruginosa Psl and PcrV bispecific antibody.Bispecific antibody can be for example as about
500mg to about 3000mg, such as the single dose of 500mg, 600mg, 700mg, 750mg, 1000mg, 1500mg or 3000mg come
It gives.In certain aspects, bispecific antibody can be given as IV infusions.In certain aspects, by P. aeruginosa
Microbial disease is iatrogenic or iatrogenic.In greater detail such as elsewhere herein, susceptible human experimenter is
In suffer from can be treated by method provided herein or the risk of preventible disease under but when giving do not have disease disease
The people of shape;Or the people by the microbial disease of P. aeruginosa for suffering from and needing to treat, intervene or slow down.This method is further
Including being monitored in such as 1 day, 3 days, 5 days, 8 days, 10 days, 15 days, 21 days, 28 days or 30 days after giving bispecific antibody
The disease symptoms of subject.In one embodiment, this method includes monitoring subject at least about 21 days from giving the same day
Symptom.Symptom associated with pneumonia is known in the art, and in the example that is described below of exemplary symptom.According to
The method, if 1 day, 3 days, 5 days, 8 days, 10 days, 15 days, 21 days, 28 days or 30 days for example after giving, subject keeps nothing
Symptom (if subject is asymptomatic when giving) or the symptom shown are not so good as expected disease when unused MEDI3902 treatments
Shape is serious like that, then human experimenter is by successful treatment.In one embodiment, if 7 days after giving, subject keeps nothing
Symptom (if subject is asymptomatic when giving) or the symptom shown are not so good as expected disease when unused MEDI3902 treatments
Shape is serious like that, then human experimenter is by successful treatment.In one embodiment, if 21 days after giving, subject keeps
Asymptomatic (if subject is asymptomatic when giving) or the symptom shown are not so good as expected when unused MEDI3902 treatments
Symptom is serious like that, then human experimenter is by successful treatment.In another embodiment, if 28 days or 30 days after giving,
Subject keeps asymptomatic (if subject is asymptomatic when giving) or the symptom shown not as good as unused MEDI3902 is controlled
Expected symptom is serious like that when treatment, then human experimenter is by successful treatment.
In certain aspects, need according to the bispecific antibody that method in this is given to include specific binding Psl
Binding structural domain, the binding structural domain include one group of complementary determining region (CDR):HCDR1-Psl、HCDR2-Psl、HCDR3-Psl、
LCDR1-Psl, LCDR2-Psl and LCDR3-Psl, wherein HCDR1-Psl have amino acid sequence SEQ ID NO:10,
HCDR2-Psl has amino acid sequence SEQ ID NO:11, HCDR3-Psl have amino acid sequence SEQ ID NO:12,
LCDR1-Psl has amino acid sequence SEQ ID NO:13, LCDR2-Psl have amino acid sequence SEQ ID NO:14, and
LCDR3-Psl has amino acid sequence SEQ ID NO:15;And the binding structural domain of specific binding PcrV, the integrated structure
Domain includes HCDR1-PcrV, HCDR2-PcrV, HCDR3-PcrV, LCDR1-PcrV, LCDR2-PcrV and LCDR3-PcrV,
Middle HCDR1-PcrV has amino acid sequence SEQ ID NO:2, HCDR2-PcrV have amino acid sequence SEQ ID NO:3,
HCDR3-PcrV has amino acid sequence SEQ ID NO:4, LCDR1-PcrV have amino acid sequence SEQ ID NO:6,
LCDR2-PcrV has amino acid sequence SEQ ID NO:7, and LCDR3-PcrV has amino acid sequence SEQ ID NO:8.
In embodiment, bispecific antibody has heavy chain and light chain.Heavy chain includes Formula V H-CH1-H1-L1-S-L2-H2-CH2-CH3,
Wherein VH is comprising amino acid sequence SEQ ID NO:1 anti-PcrV heavy-chain variable domains, wherein CH1 are heavy chain constant region knots
Structure domain -1, H1 is the first heavy chain hinge region segment, and L1 is the first connector, and S is comprising amino acid sequence SEQ ID NO:9 it is anti-
Psl ScFv molecules, L2 are the second connectors, and H2 is the second heavy chain hinge region segment, and CH2 is heavy-chain constant domains -2, and
CH3 is heavy-chain constant domains -3.Light chain includes Formula V L-CL, and wherein VL is comprising amino acid sequence SEQ ID NO:5 it is anti-
PcrV light variable domains, and CL includes antibody light chain κ constant regions or the areas antibody light chain λ.In certain aspects, CH1 can
To include amino acid sequence SEQ ID NO:16.In certain aspects, L1 and L2 can be same or different, and can be with
It is independently 0,1,2,3,4 or 5 (SEQ ID NO comprising (a) [GGGGS] n, wherein n:23);(b) [GGGG] n, wherein n be 0,
1,2,3,4 or 5 (SEQ ID NO:24);Or the combination of (a) and (b).In certain aspects, H1 can include amino acid sequence
EPKSC(SEQ ID NO:17).In certain aspects, H2 can include amino acid sequence DKTHTCPPCP (SEQ ID NO:
18).In certain aspects, CH2-CH3 can include amino acid sequence SEQ ID NO:19.In certain aspects, CH2-CH3 can
To include amino acid sequence SEQ ID NO:20.In certain aspects, the heavy chain of bispecific antibody can include amino acid sequence
Arrange SEQ ID NO:21, and light chain includes amino acid sequence SEQ ID NO:22.
For the bispecific antibody in method provided herein can for example as about 500mg to about 3000mg, such as
The single dose of 500mg, 600mg, 700mg, 750mg, 1000mg, 1500mg or 3000mg is given.
In some embodiments, the serum target level of bispecific antibody or its antigen-binding fragment is in about 1 μ g/mL
To about 10 μ g/mL, about 2 μ g/mL to about 9 μ g/mL, about 3 μ g/mL to about 8 μ g/mL, about 4 μ g/mL to about 7 μ g/mL, about 5 μ g/mL
Extremely to about 6 μ g/mL, about 5 μ g/mL to about 7 μ g/mL, 5 μ g/mL to about 8 μ g/mL, 5 μ g/mL to about 9 μ g/mL or about 5 μ g/mL
In the range of about 10 μ g/mL.In other embodiments, the serum target level of bispecific antibody or its antigen-binding fragment is
In about 1 μ g/mL to about 6 μ g/mL, about 1 μ g/mL to about 5 μ g/mL, about 1 μ g/mL to about 4 μ g/mL, about 1 μ g/mL to about 3 μ g/
In the range of mL or about 1 μ g/mL to about 2 μ g/mL.In one embodiment, bispecific antibody or its antigen-binding fragment
Serum target level is at least 1.7 μ g/mL.In another embodiment, the blood of bispecific antibody or its antigen-binding fragment
Clear target level is at least 5.3 μ g/mL.It is expected that about 1.7 μ g/mL serum target levels prevent or treat by>The copper of 80%-90%
Infection caused by green pseudomonad strain.It is expected that about 5.3 μ g/mL serum target levels are prevented or are treated false by most indomitable verdigris
Infection caused by aeromonas strain (such as high toxicity and to the drug resistant bacterial strain of antibiotic, such as ARC3928 and ARC3502).
In certain aspects, it can be given as IV infusions for the bispecific antibody in method provided herein.
Method is suitable for susceptible human experimenter as described elsewhere herein provided herein.Example includes that will live
Institute, it is current be hospitalized, be hospitalized recently, being hospitalized recently, will, the current or last subject using mechanical respirator or combinations thereof.
In some cases, can be in intensive care unit (ICU) in hospital.If necessary, mechanical ventilation can be passed through
Intubation (such as passing through tracheal strips or nasotracheal tube) is carried out by tracheostoma.It will or currently or recently carry out machinery
The patient of ventilation can have the increased risk for suffering from respiratory tract infection (such as pneumonia, such as pseudomonas aeruginosa pneumonia).
In the case of indicating mechanical ventilation, the giving for bispecific antibody that method as disclosed provides can for example work as
It is preceding when carrying out mechanical ventilation, no longer need after mechanical ventilation or combinations thereof in the case of reduce the risk for suffering from pneumonia.
In certain aspects, when giving the bispecific antibody, the subject is in respiratory tract (such as lower respiratory tract)
Field planting has pseudomonas aeruginosa.In certain aspects, the previous day for giving bispecific antibody, two days, three days or four days, by
The respiratory tract field planting of examination person has pseudomonas aeruginosa.Field planting can be for example by 6 hours before giving bispecific antibody, 12
Pseudomonas aeruginosa is detected to measure in tracheal aspirate in hour, 24 hours, 48 hours, 72 hours or 96 hours.Yu
In some aspects of this method provided, which does not receive to be considered before giving the bispecific antibody for should be by
The active antibiotic of pseudomonas aeruginosa strains that examination person is colonized.In certain aspects, the bispecific is being given
When antibody, in addition the respiratory tract of the subject can be colonized staphylococcus aureus.
In certain aspects, subject does not have symptoms of pneumonia when giving bispecific antibody.Symptom can be according to clinic
Pulmonary infection scoring (CPIS) measures.For example, if 24 hours subjects have and are less than before giving bispecific antibody
6 CPIS may infer that shortage symptom.
Method, which is included in, provided herein gives the disease symptoms that bispecific antibody monitors subject later, such as pneumonia
Symptom.In certain aspects, can by chest X-ray, observe pneumonia breathing S or S, to pneumonia carry out microorganism
Learn confirm or any combination thereof monitor the pneumonia of subject.Such as it is consistent with pneumonia new when being observed on chest X-ray
Or deterioration infiltration when, show at least two slight or at least one main pneumonia breathing signs or disease as subject
When shape, when the sample obtained from subject is positive to the culture of pseudomonas aeruginosa, or any combination thereof when, it may be determined that
Subject suffers from pneumonia.In certain aspects, sample is the respiratory secretions of subject.Respiratory secretions can pass through gas
Pipe in be sucked out, by using bronchoalveolar lavage bronchoscopy, by be intubated subject use it is shielded
Sample swipe sample, or any combination thereof obtained from the phlegm of expectoration.
Body temperature, the body core less than about 35 DEG C that the slight breathing S or S of pneumonia includes but not limited to greater than about 38 DEG C
Temperature, greater than about 10,000 cells/cubic millimeter (mm3) white blood cell count, be less than about 4,500 cell/mm3It is white
Blood count, the production of the band-like core neutrophil counts for being greater than about 15%, new suppurative tracheae endocrine or phlegm
Raw, new auscultated results, dull percussion note, neopathy cough, have difficulty in breathing, be short of breath, hypoxemia.
The acute change that the main breathing S or S of pneumonia can include but is not limited to carry out in support system of ventilating is to enhance
Oxygen closes, which includes maintaining PaO2/FiO2Ratio is less than about 240mmHg at least four hours, maintains PaO2/FiO2Ratio
Greater than about 50mmHg at least four hours, the necessity for starting or restarting mechanical ventilation in the subject of on-mechanical ventilation,
Or any combination thereof.The microbiology of pneumonia, which confirms, can include but is not limited to cultivate the breathing being positive to pseudomonas aeruginosa
Road sample, the blood cultures being positive to pseudomonas aeruginosa, the liquor pleurae aspirate being positive to pseudomonas aeruginosa or
Lung tissue culture, or any combination thereof.
In certain aspects, the method that present disclosure provides may further include before giving bispecific antibody, together
When and/or backward subject give antibiotic.Suitable antibiotic can include but is not limited to aminoglycoside, Ticarcillin,
Urea groups penicillin, Ciprofloxacin, Cefepime, gentamicin, amikacin, tobramycin, cefotaxime, aztreonam, cephalo
Thiophene oxime, or any combination thereof.Health care provider can readily determine that suitable dosage and treatment time.In some aspects
In, the pseudomonas aeruginosa strains that subject is colonized are to selecting the antibiotic sensitive for giving.However, in other respects
In, the pseudomonas aeruginosa strains that subject is colonized are to selecting one or more available antibiotics resistances for giving
Or part drug resistance.In preclinical study, for example, MEDI3902 shows the antibiotherapy for pseudomonas aeruginosa pneumonia
Enhance from the other collaboration of the different antibiotics for antibiotics sensitivity and antibiotic resistance pseudomonas aeruginosa.
In certain aspects, the method that present disclosure provides may further include before giving bispecific antibody, together
When and/or backward subject give antihistaminic.Suitable antihistaminic can include but is not limited to diphenhydramine, chlorine Maas
Spit of fland, dexchlorpheniramine, azelastine, cetirizine, Desloratadine, fexofenadine, levocetirizine, Loratadine, Austria
Luo Tading, or any combination thereof.Health care provider can readily determine that suitable dosage and treatment time.
In certain aspects, the method that present disclosure provides includes monitoring the serum medicine of the bispecific antibody of subject for dynamic
Mechanics, bispecific antibody tracheae secretion pharmacokinetics, or combinations thereof.Subject can give bispecific antibody it
For example, at least about 1 μ g/ are maintained in the 7th day afterwards, the 14th day, the 21st day, the 28th day, the 30th day, the 35th day, the 42nd day or the 49th day
ML, at least about 2 μ g/mL, at least about 3 μ g/mL, at least about 4 μ g/mL, at least about 5 μ g/mL or at least about 5.3 μ g/mL or more
Bispecific antibody serum levels.For example, subject can the 7th day after giving bispecific antibody, the 14th day,
At least about 1.7 μ g/mL or at least about 5.3 μ g/mL are maintained in 21 days, the 28th day, the 30th day, the 35th day, the 42nd day or the 49th day
Or more bispecific antibody serum levels.Monoclonal based on the directed toward bacteria pathogen observed in ICU patient is anti-
The removing of body (such as MEDI4893) increases, for using the ICU patient of mechanical ventilation after the single dose of MEDI3902
Pharmacokinetic modeling.Prediction single dose 1500mg MEDI3902 exist>Continue to maintain about for >=21 days in 90% subject
The serum of 1 μ g/mL exposes.Prediction single dose 3000mg MEDI3902 exist>Continue to maintain about for >=21 days in 90% subject
The serum of 1.7 μ g/mL exposes.Pharmacokinetics based on healthy volunteer is not (for example, as being observed in ICU patient
Such removing increases), it is contemplated that the single dose of 500mg, 1500mg or 3000mg exist>Continue >=21 days in 90% subject
The serum of about 1 μ g/mL is maintained to expose, such as>Continue to maintain about 1.7 μ g/mL in >=21 days in 90% subject, such as exist>
Continue to maintain about 5.3 μ g/mL in >=21 days in 90% subject.Certainly, the serum levels of bispecific antibody will supervised entirely
Variation in the survey phase, and about 100 μ g/mL, about 200 μ g/mL, about can be reached according to the dosage of bispecific antibody to be administered
The maximum concentration or C of 300 μ g/mL, about 400 μ g/mL, about 500 μ g/mL or the greater than about bispecific antibody of 600 μ g/mLmax。
In certain aspects, area (AUC under can measuring from zero to the Cot curve of infinite duration∞).For example, for
The bispecific antibody of 1500mg dosage, AUC∞Can be for example, about 2000 μ g days/mL to about 6000 μ g days/mL, such as
About 4000 μ g days/mL.In certain aspects, serum end-stage half-life period can be measured.In certain aspects, stable state can be measured
Distribution volume (Vdss).Can the 7th day after giving bispecific antibody, the 14th day, the 21st day, the 28th day, the 30th day,
35 days, the 42nd day, the 49th day or the longer time interior pharmacokinetic parameter for monitoring subject.In certain aspects, Ke Yi
Subject is monitored in 21st day.In certain aspects, subject can be monitored in the 49th day.
Example disclosed below is only representative.Therefore, concrete structure, function and the journey disclosed in the following example
Sequence details is understood not to restrictive.
Example
Example 1:1 clinical trial phase is studied
Carry out 1 phase, in the mankind, random first, double blind, placebo dose escalation study, research assessment
MEDI3902 singles rise safety and tolerance of the IV dosage in health adult subject.It is 250mg in acceptable dose
(n=3), 42 subjects of the MEDI3902 of 750mg (n=15), 1500mg (n=15) or 3000mg (n=9) and receive peace
In 14 subjects for consoling agent, adverse events (AE), PK and ADA data are collected, until last time study visit is (60 after administration
It/the 61st day).All AE in MEDI3902 groups and placebo the two are 1 grade or 2 grades in terms of seriousness.It is most frequent
The adverse events of report are 1 grade or 2 grades infusion correlated response (in entire MEDI3902 groups 15/42 subject'ss [35.7%];
Do not have in placebo) and 1 grade or 2 grades headache (in entire MEDI3902 groups 6/42 subject's [14.3%];Placebo
2/14 subject's [14.3%] in group).Adverse events (AESI) of special interest include infusion correlated response event (whole
15/42 subject [35.7.7%] in a MEDI3902 groups;Placebo does not have), which passes through use
Diphenhydramine in treatment simultaneously slows down infusion velocity to slow down.Most of events of infusion correlated response subside or later during infusion
Subside immediately or subsided at second day.Due to being transfused correlated response, two subjects (1 in 750mg MEDI3902 dosage groups
1 subject in position subject and 3000mg dosage groups) do not complete administration.Serious adverse events (SAE) are not reported.
In 1 phase was studied, the PK and immunogenicity of MEDI3902 are had studied in adult healthy volunteers.It receives before administration
Collect blood sample and up to 60 days different time points collect blood sample upon administration, in quantitative serum
MEDI3902 concentration simultaneously detects the ADA for being directed to MEDI3902.After venoclysis, MEDI3902 is in health adult subject
Show cutting edge aligned PK.Peak serum levels may be immediately observed that after infusion, and be declined as time goes by with double exponential manners.
MEDI3902 concentration in 250mg dosage groups can measure in 42 days upon administration, and other high dose groups upon administration 60
There is measurable serum-concentration in it.For most of subjects in this group, single dose 750mg IV are maintained above
The serum of 5.3 μ g/mL of target level exposes, and continues 28 days.MEDI3902 in serum expose with substantially with dose proportional
Mode increases to 1500mg from 250mg, and increases to 3000mg from 1500mg in a manner of being slightly less than with dose proportional.
CmaxFrom 250mg when 100 μ g/mL increase to 1500mg when 468 μ g/mL, and 838 μ g/mL when increasing to 3000mg.From
Zero to area (AUC under the Cot curve of infinite duration∞) in a manner of with dose proportional from 250mg when 694 μ g
It/4246 μ gs days/mLs of mL when increasing to 1500mg.AUC when 3000mg∞For 6540 μ g days/mL.Estimate serum end eventually
Half-life period is 7-9 days.Vdss (Vdss) it is 3.4-4.9L, this indicates the limited distribution in intravascular space.42 by
In examination person, the 61st day test ADA is positive upon administration for 1 subject (3000mg) in group 4.MEDI3902 subjects herein
In serum-concentration reduce rapidly within 45 days upon administration, and the 60 days water for being brought down below lower limit of quantitation (LLOQ) upon administration
Flat, this shows influences of the ADA to MEDI3902PK.
It has been found that MEDI3902 is typically safety in initial 1 phase is studied.
Example 2:2b clinical trial phases are studied
In 2 phases, random, double blind, placebo, single dose, dosage range concept prove, mainly in Europe
About 120 places recruit and about 429 subjects and be administered.Subject will be with 1:1:1 ratio is randomly assigned to receive
The single IV dosage or placebo of 1500mg or 3000mg MEDI3902.Dosage regimen can also become 1500mg (or
3000mg) 1 between the single IV dosage or placebo of MEDI3902:1 randomization.Randomization will according to geographic area and according to
Whether subject receives resisting pseudomonas aeruginosa antibiosis extract for treating (duration≤72 hour) before randomization in 96 hours
It is layered.Subject will be tracked to the 50th day (49 days after research product is given) (Fig. 1).
In order to recruit, need subject over 18 years old or more, in intensive care unit, front cannula and machinery it is logical
Gas and maintain intubation and mechanical ventilation at least 3 days when it is contemplated that entering research.Such as by having in before randomization 36 hours
Having proves the tracheal samples that pseudomonas aeruginosa is positive, and subject must also be colonized in lower respiratory tract has verdigris false
Monad, but currently without the relevant disease of pseudomonas aeruginosa.The subject with pneumonia recession evidence can be recruited.
If subject suffers from acute confirmation or doubtful pseudomonas disease when recruiting or before receiving MEDI3902,
Then they disqualification participate in.If if subject is previously-accepting to cross monoclonal antibody, subject in MEDI3902 administrations preceding 24
In hour with six or bigger clinical lung's Sepsis Score (CPIS) or if subject when being randomized with being more than or
Acute physiology and Chronic Health Evaluation-II (APACHE-II) scorings equal to 25 or the SOFA scorings more than or equal to 12, then
They also disqualification participate in.Activity pulmonary disease (such as active tuberculosis with the ability that will damage diagnosis of pneumonia
Or fungal disease, obstructive lung cancer, a large amount of pleural effusions or pyothorax, cystic fibrosis or acute respiratory distress syndrome are with lung
" albefaction ") subject be not eligible for.The subject of tracheostoma is relied on before being admitted to hospital and is burnt more than 40% body surface
Subject be not eligible for.In addition, if subject receives resisting pseudomonas aeruginosa antibiotic before randomization in 96 hours
More than 72 hours, then these subjects were not eligible for, and wherein the antibiotic is considered to have the copper being colonized for subject
The activity of green pseudomonad strain, or wherein expection persistently receives the resisting pseudomonas aeruginosa antibiotic.
Subject will be probabilistically assigned to receive to be transfused the single dose 1500mg given via IV on day 1
MEDI3902,3000mg MEDI3902 or placebo.All subjects will be 15-30 points before the infusion of drug that begins one's study
Take antihistaminic in clock in advance, such as 50mg diphenhydramines IV, clemastine 2mg IV or dexchlorpheniramine 5mg IV (or
Another antihistamine formulations utilized in common clinical practice for managing acute allergic reaction).Subject can be authorized to exist
It is in addition taken medicine in advance with the following terms before the product that begins one's study infusion:Paracetamol 650mg takes orally and/or methylprednisolone
20mg IV combined with antihistaminic or antihistaminic and famotidine 20mg it is oral with or without paracetamol and/or
Methylprednisolone combines.
The primary efficacy endpoint of this research is the patients with mechanical ventilation under pseudomonas aeruginosa Nosocomial pneumonia risk
After the MEDI3902 of single dose in 21 days (the 22nd day) by the incidence of the microbial Nosocomial pneumonia of P. aeruginosa.
Based on the data from 1 phase research (referring to example 1), the PK/PD data from preclinical pharmacology research (for example, muroid copper
EC in the fatal pneumonia model of green pseudomonad induction90), other monoclonal antibodies based on directed toward bacteria pathogen exist
Intermediate value (range) time of the increased PK modelings (Fig. 2) of removing observed in ICU patient and the VAP breaking-outs about 10 days
Clinical report, to select dosage level.21 day period will be there is still a need for after entire administration by the subject of some mechanical ventilations
Mechanical ventilation, but some subjects may will disconnect lung ventilator during this period.Since subject no longer needs at them behind these
It wants to occur by the microbial Nosocomial pneumonia of P. aeruginosa after mechanical ventilation, so assessment is carried out when recruiting
Curative effect in the subject of machine ventilation, but regardless of being to maintain during they upon administration 21 day period or disconnection machine
Tool is ventilated.Secondary efficacy terminal is by independent assessment when carrying out mechanical ventilation by the microbial Nosocomial pneumonia of P. aeruginosa
Incidence, and no longer need in 21 days upon administration after mechanical ventilation by the microbial Nosocomial pneumonia of P. aeruginosa
Incidence.
Primary safety terminal will evaluate TEAE, TESAE and AESI upon administration in 49 days.
Secondary endpoints (the MEDI3902 serum-concentrations, PK parameters after administration in 49 days and the ADA responses to MEDI3902)
It is designed to the presence of evaluation MEDI3902 in vivo.
Data analysis will be completed to execute after the research in all subjects.Will to last position in 49 days upon administration by
All data that examination person completes to collect after follow-up carry out effect, pharmacokinetics (PK), anti-drug antibodies (ADA) and safety
Property analysis, with prove single IV dosage 1500mg (and may be for 3000mg) MEDI3902 have acceptable safety
Feature and can upon administration in 21 days reduce pseudomonas aeruginosa pneumonia in intensive care unit (ICU) and under exhale
It inhales to be colonized in road and has the incidence in the mechanical ventilation subject of pseudomonas aeruginosa (not considering mechanical ventilation when diagnosis).
On day 2, the 4th (± 1) day, the 8th (± 1) day, the 15th (± 1) day, the 29th (± 1) day and the 50th (± 1) day
The microbiology evaluation that tracheal aspirate sample is colonized for pseudomonas aeruginosa is collected, condition is that subject keeps intubation.
Monitor the clinical symptoms of the pneumonia and other serious charrin diseases of subject daily during being hospitalized, and
It is monitored according to the symptom after discharge.At these, which includes physical examination and vital sign assessment.In hospital stay
Between, CPIS is evaluated daily, while subject keeps mechanical ventilation.
For the subject with doubtful serious charrin disease, evaluated on the day of morbidity clinical symptoms (CPIS,
SOFA, physical examination and vital sign), and then evaluate daily until subsiding.Divide on the day of morbidity and in following two days
Analyse the blood sample of all subjects with doubtful serious charrin disease.It is being in sun to pseudomonas aeruginosa pneumonia
Property subject in be every other day repeated once blood sampling analysis, until they are negative to pseudomonas aeruginosa.It is falling ill
The same day and it is two days following in analyze all intubations with doubtful serious charrin disease subject tracheae and
Bronchial aspirates.In the subject being positive to pseudomonas aeruginosa pneumonia, it is repeated once tracheae daily or bronchus is inhaled
Go out object analysis, until subsiding.Analysis suffers from doubtful serious charrin disease on the day of morbidity and in following two days
It is not intubated subject's expectoration (except non-executing bronchoscopy is for clinical management and available BAL or PSB samples)
Phlegm.In the subject being positive to pseudomonas aeruginosa pneumonia, it is every other day repeated once the analysis of expectoration phlegm, until subsiding.
Chest X-ray is executed to the subject with doubtful serious charrin disease on the day of morbidity.Being indicated such as clinic
Chest X-ray is repeated in the subject of pneumonia with confirmation, until subsiding.
When diagnosing pseudomonas aeruginosa pneumonia in the subject of mechanical ventilation, it is following that diagnostic criteria requires subject to prove
Radiology, clinic and microbiology neopathy symptom/sign are not as any other non-infectious situation.
1. radiology standard:
A. new or deterioration the infiltration consistent with pneumonia is (by qualification on the chest X-ray obtained in 24 hours after an event
Radiologist diagnoses)
And
2. clinical criteria:Neopathy is at least2A following secondary breathing S or S or1A main breathing sign or disease
Shape:
Minor criteria:
B. the whole body sign infected (one of the following is multiple):Abnormal body temperature (oral temperature or tympanic temperature>38 DEG C or body
Nuclear temperature >=38.3 DEG C or hypothermia, are defined as core temperature<35 DEG C) and/or abnormal WBC countings (WBC countings>10,
000 cell/mm3, WBC count<4,500 cell/mm3Or>15% band-like core neutrophil)
C. the generation of new suppurative tracheae endocrine
The d. new Physical examination results consistent with pneumonia/pulmonary consolidation, such as auscultated results (such as rale, dry rale, bronchus
Breath sound) or dull percussion note
Main standard:
E. acute change is carried out in support system of ventilating to enhance oxygen conjunction, such as by identified below:
i.PaO2/FiO2Ratio<240mmHg is maintained at least 4 hours, or
ii.PaO2/FiO2Reduction >=50mmHg is maintained at least 4 hours
And
3. microbiology confirms (being obtained in 24 hours after an event occurs):In below at least1It is a:
F. the breath sample being positive to pseudomonas aeruginosa culture, which is included in intubation subject, to be sucked out or is led to by tracheal strips
Cross the respiratory secretions sample that the bronchoscopy carried out via BAL or PSB samplings obtains.It is not intubated but is meeting machinery
It ventilates in the subject of protocol definition, the sample of expectoration phlegm is acceptable.
G. the blood cultures (and without apparent main infection source outside lung) being positive to pseudomonas aeruginosa
H. liquor pleurae aspirate or lung tissue culture (the only conduct being positive to pseudomonas aeruginosa during pneumonia is broken out
A part for the necessary clinical management of subject obtains).
If subject be intubated by tracheal strips or nasotracheal tube and receive positive airway pressure support, or if they
Tracheal strips or nose tracheae are not intubated, but the positive airway pressure of 8 hours or longer time were needed within past 24 hours, then it is assumed that tested
Person's mechanical ventilation.
When diagnosing pseudomonas aeruginosa pneumonia in the subject of non-mechanical ventilation, diagnostic criteria require subject prove with
Lower radiology, clinic and microbiology neopathy symptom/sign are not as any other non-infectious situation.
4. radiology standard:
I. new or deterioration the infiltration consistent with pneumonia is (by qualification on the chest X-ray obtained in 24 hours after an event
Radiologist diagnoses)
And
5. clinical criteria:Neopathy is at least2A following secondary breathing S or S or1A main breathing sign or disease
Shape:
Minor criteria:
J. the whole body sign infected (one of the following is multiple):Abnormal body temperature (oral temperature or tympanic temperature>38 DEG C or body
Nuclear temperature >=38.3 DEG C or hypothermia, are defined as core temperature<35 DEG C) and/or abnormal WBC countings (WBC countings>10,
000 cell/mm3, WBC count<4,500 cell/mm3Or>15% band-like core neutrophil)
K. the cough (or cough aggravated) of neopathy
L. the generation of suppurative phlegm
The m. new Physical examination results consistent with pneumonia/pulmonary consolidation, such as auscultated results (such as rale, dry rale, bronchus
Breath sound), dull percussion note or pectoralgia
N. it has difficulty in breathing, (respiratory rate of being short of breath>30 beats/min) or such as undefined hypoxemia:
Iii. if being less than baseline, indoors oxygen (O in air2) saturation degree<90% or PaO2<60mmHg, or
Iv. it needs to start or increase the O for continuing (>=3 hours)2Supplement is with baseline O before maintenance event2Saturation degree
Main standard:
O. it needs to start no-wound mechanical ventilation due to respiratory failure or respiratory state deterioration or restarts Mechanical ventilation
And
6. microbiology confirms (event obtains after occurring in 72 hours):In below at least1It is a:
P. the respiratory tract sample being positive is cultivated to pseudomonas aeruginosa.Phlegm or (only necessary as subject including expectoration
Clinical management a part obtain) pass through via BAL or PSB sampling carry out bronchoscopy obtain respiratory tract secrete
Object sample
Q. the blood cultures (and without other apparent main infection sources outside lung) being positive to pseudomonas aeruginosa
R. the liquor pleurae aspirate or lung tissue culture being positive to pseudomonas aeruginosa (are only used as that subject is necessary to be faced
A part for bed management obtains).
Need not just ventilate support when tracheal strips or nasotracheal tube are not in appropriate location and subject at least 8 is small
When, it is not considered as subject's mechanical ventilation.
The incidence of pseudomonas aeruginosa pneumonia in 21 days after being administered is calculated to be proven to give 1500mg or 3000mg
MEDI3902 reduces the incidence of pseudomonas aeruginosa pneumonia.Mechanical ventilation subject and no longer need mechanical ventilation by
In examination person, by compare administration after in 21 days pseudomonas aeruginosa pneumonia incidence.
The chronic disease of comment adverse events and neopathy is safe to be proven to give 1500 or 3000mgMEDI3902.
Example 3:In the case where relatively low bacterium is born, MEDI3902 reduces the lethality in acute pneumonia model
The vivo effect given using acute pneumonia scale-model investigation MEDI3902 in mouse.With reduction concentration
MEDI3902 (1.0mg/kg, 0.5mg/kg or 0.2mg/kg) or isotype controls IgG antibody (negative control, 0.75mg/kg)
Intraperitoneal injection (IP) mouse group (n=6).Twenty four hours after the treatment, by all mouse with 2 × 105CFU P. aeruginosas
6206 (1 × LD of bacteria strain100) carry out intranasal infection.As shown in figure 3,120 hours after infection, the animal of all control treatments
All die of infection.However, MEDI3902 display protections completely under all dosage, even if in 1 × LD100It is lower be also in this way, this
Show that the relatively low target serum levels of 1.7 μ g/mL in the mankind will provide the protection for being directed to most of pseudomonas aeruginosa strains.
The width and range of present disclosure should be not limited to any of example embodiments described above, and should be only
It is limited according to following claims and their equivalent.
Sequence table
<110>Medical immunology Co., Ltd(MEDIMMUNE, LLC)
<120>Method for preventing Nosocomial pneumonia
<130> PSEUD-200-WO-PCT
<140>
<141>
<150> 62/260,935
<151> 2015-11-30
<160> 24
<170>PatentIn 3.5 editions
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Ser Ala Ile Thr Met Ser Gly Ile Thr Ala Tyr Tyr Thr Asp Asp Val
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Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
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Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Lys Glu Glu Phe Leu Pro Gly Thr His Tyr Tyr Tyr Gly Met Asp
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Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
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Ser Arg Val Thr Ile Ser Gly Asp Thr Ser Lys Lys Gln Phe Ser Leu
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Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
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Arg Ala Asp Trp Asp Arg Leu Arg Ala Leu Asp Ile Trp Gly Gln Gly
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Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
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Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr
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Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
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Thr Cys Arg Ala Ser Gln Ser Ile Arg Ser His Leu Asn Trp Tyr Gln
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Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Gly Ala Ser Asn
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Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
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Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
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Asp Lys Thr His Thr Cys Pro Pro Cys Pro
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Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
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Pro Lys Asp Thr Leu Xaa Ile Xaa Arg Xaa Pro Glu Val Thr Cys Val
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Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
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Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
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Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
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Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
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Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
130 135 140
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145 150 155 160
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165 170 175
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210 215
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Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
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Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
115 120 125
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
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Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
145 150 155 160
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
165 170 175
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
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Lys Ser Leu Ser Leu Ser Pro Gly Lys
210 215
<210> 21
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Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Thr Met Ser Gly Ile Thr Ala Tyr Tyr Thr Asp Asp Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Glu Glu Phe Leu Pro Gly Thr His Tyr Tyr Tyr Gly Met Asp
100 105 110
Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys
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Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
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Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
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Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
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Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro
210 215 220
Lys Ser Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln
225 230 235 240
Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser
245 250 255
Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Pro Tyr Tyr Trp Thr
260 265 270
Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Leu Ile Gly Tyr Ile
275 280 285
His Ser Ser Gly Tyr Thr Asp Tyr Asn Pro Ser Leu Lys Ser Arg Val
290 295 300
Thr Ile Ser Gly Asp Thr Ser Lys Lys Gln Phe Ser Leu Lys Leu Ser
305 310 315 320
Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala Asp
325 330 335
Trp Asp Arg Leu Arg Ala Leu Asp Ile Trp Gly Gln Gly Thr Met Val
340 345 350
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
355 360 365
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro
370 375 380
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
385 390 395 400
Ala Ser Gln Ser Ile Arg Ser His Leu Asn Trp Tyr Gln Gln Lys Pro
405 410 415
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Gly Ala Ser Asn Leu Gln Ser
420 425 430
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
435 440 445
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
450 455 460
Gln Gln Ser Thr Gly Ala Trp Asn Trp Phe Gly Cys Gly Thr Lys Val
465 470 475 480
Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr
485 490 495
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
500 505 510
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
515 520 525
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
530 535 540
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
545 550 555 560
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
565 570 575
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
580 585 590
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
595 600 605
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
610 615 620
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
625 630 635 640
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
645 650 655
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
660 665 670
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
675 680 685
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
690 695 700
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
705 710 715 720
<210> 22
<211> 214
<212> PRT
<213>Artificial sequence
<220>
<223>The description of artificial sequence:Synthesis polypeptide
<400> 22
Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Tyr Asn Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 23
<211> 25
<212> PRT
<213>Artificial sequence
<220>
<223>The description of artificial sequence:Synthetic linker sequence
<220>
<221>Still unclassified feature
<222> (1)..(25)
<223>This sequence can cover 0-5 ' Gly Gly Gly Gly Ser ' repetitive units
<400> 23
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25
<210> 24
<211> 20
<212> PRT
<213>Artificial sequence
<220>
<223>The description of artificial sequence:Synthetic linker sequence
<220>
<221>Still unclassified feature
<222> (1)..(20)
<223>This sequence can cover 0-5 ' Gly Gly Gly Gly ' repetitive units
<400> 24
Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly
1 5 10 15
Gly Gly Gly Gly
20
Claims (35)
1. a kind of prevention or the method for the treatment of the hospital-acquired infection in susceptible human experimenter, this method include to the subject to
Give the bispecific antibodies of about 500 to about 3000mg specific binding pseudomonas aeruginosa Psl and PcrV, and from giving the same day
The symptom of the subject is monitored in 21 days started;21 days wherein after giving, the subject keep it is asymptomatic or relative to
The group for giving the susceptible human experimenter of placebo shows the smaller symptom of seriousness;
Wherein the bispecific antibody includes the binding structural domain of specific binding pseudomonas aeruginosa Psl, the binding structural domain
Including one group of complementary determining region (CDR):HCDR1-Psl, HCDR2-Psl, HCDR3-Psl, LCDR1-Psl, LCDR2-Psl and
LCDR3-Psl, wherein HCDR1-Psl have amino acid sequence SEQ ID NO:10, HCDR2-Psl have amino acid sequence SEQ
ID NO:11, HCDR3-Psl have amino acid sequence SEQ ID NO:12, LCDR1-Psl have amino acid sequence SEQ ID
NO:13, LCDR2-Psl have amino acid sequence SEQ ID NO:14, and LCDR3-Psl has amino acid sequence SEQ ID
NO:15;And the binding structural domain of specific binding pseudomonas aeruginosa PcrV, the binding structural domain include one group of CDR:
HCDR1-PcrV, HCDR2-PcrV, HCDR3-PcrV, LCDR1-PcrV, LCDR2-PcrV and LCDR3-PcrV, wherein
HCDR1-PcrV has amino acid sequence SEQ ID NO:2, HCDR2-PcrV have amino acid sequence SEQ ID NO:3,
HCDR3-PcrV has amino acid sequence SEQ ID NO:4, LCDR1-PcrV have amino acid sequence SEQ ID NO:6,
LCDR2-PcrV has amino acid sequence SEQ ID NO:7, and LCDR3-PcrV has amino acid sequence SEQ ID NO:8.
2. the method as described in claim 1, the wherein hospital-acquired infection are pneumonia, bacteremia, infection of bone, the infection of joint, skin
Skin infection, infection of burn, wound infection, or any combination thereof.
3. method as claimed in claim 2, the wherein hospital-acquired infection are pneumonia.
4. method as claimed any one in claims 1 to 3, the wherein pneumonia are microbial by P. aeruginosa.
5. method according to any one of claims 1 to 4, wherein the bispecific antibody of about 1500mg or about 3000mg
It is given.
6. the method as described in any one of claim 1 to 5, wherein CH1 include amino acid sequence SEQ ID NO:16.
7. such as method according to any one of claims 1 to 6, wherein L1 and L2 are same or different, and independently
Including (a) [GGGGS] n, wherein n is 0,1,2,3,4 or 5 (SEQ ID NO:23);(b) [GGGG] n, wherein n are 0,1,2,3,4
Or 5 (SEQ ID NO:24);Or the combination of (a) and (b).
8. the method as described in any one of claim 1 to 7, wherein H1 include amino acid sequence EPKSC (SEQ ID NO:
17)。
9. such as method described in any item of the claim 1 to 8, wherein H2 includes amino acid sequence DKTHTCPPCP (SEQ ID
NO:18)。
10. method as claimed in any one of claims 1-9 wherein, wherein CH2-CH3 include amino acid sequence SEQ ID NO:
19。
11. method as claimed in claim 10, wherein CH2-CH3 include amino acid sequence SEQ ID NO:20.
12. the method as described in any one of claim 1 to 11, the wherein heavy chain include amino acid sequence SEQ ID NO:
21, and the light chain includes amino acid sequence SEQ ID NO:22.
13. the method as described in any one of claim 1 to 12, wherein the bispecific antibody of about 500 or about 3000mg
It is given as being transfused in single dose intravenous.
14. the method as described in any one of claim 1 to 13, wherein the subject is colonized in respiratory tract and has when giving
Pseudomonas aeruginosa.
15. method as claimed in claim 14, the wherein subject do not have symptoms of pneumonia when giving.
16. such as claim 14 or method of claim 15, wherein the subject is colonized in lower respiratory tract verdigris
Pseudomonad.
17. the method as described in any one of claim 14 to 16, wherein in the previous day for giving the bispecific antibody, two
It, three days or four days, the field planting of the respiratory tract of the subject has pseudomonas aeruginosa.
18. method as claimed in claim 17, wherein be colonized by before giving the bispecific antibody 36 hours
Pseudomonas aeruginosa is detected in tracheal aspirate to measure.
19. the method as described in one in claim 14 to 18, wherein when giving the bispecific antibody, the subject
Respiratory tract in addition field planting have staphylococcus aureus.
20. the method as described in any one of claim 1 to 19, the wherein subject will be hospitalized, be currently hospitalized, live recently
Institute, using mechanical respirator, or combinations thereof.
21. method as claimed in claim 20, the wherein subject move in hospital intensive care unit (ICU).
22. the method as described in claim 20 or claim 21, the wherein subject are intubations.
23. the method as described in claim 20 or claim 21, the wherein subject pass through tracheal strips or nasotracheal tube
Carry out mechanical ventilation.
24. the method as described in any one of claim 20 to 23, wherein this gives the pneumonia wind reduced in mechanical ventilation
Danger.
25. the method as described in any one of claim 20 to 24, wherein this give reduction no longer need mechanical ventilation it
Pneumonia risk afterwards.
26. the bispecific antibody of the method as described in any one of claim 1 to 23, wherein 1500mg is given.
27. the bispecific antibody of the method as described in any one of claim 1 to 23, wherein 3000mg is given.
28. the method as described in any one of claim 1 to 27, wherein the subject is before giving the bispecific antibody
Do not receive the active antibiotic of the pseudomonas aeruginosa strains being colonized for the subject.
29. the method as described in any one of claim 1 to 28, this method further comprises giving antibiosis to the subject
Element.
30. the pseudomonas aeruginosa strains that method as claimed in claim 29, the wherein subject are colonized are anti-to this
Raw element is sensitive.
31. the pseudomonas aeruginosa strains that method as claimed in claim 29, the wherein subject are colonized are anti-to this
Raw element drug resistance or part drug resistance.
32. the method as described in any one of claim 29 to 1, wherein the antibiotic is before giving the bispecific antibody
Give, with give the bispecific antibody give, given after giving the bispecific antibody simultaneously, or any combination thereof.
33. the method as described in any one of claims 1 to 32, wherein the subject is after giving the bispecific antibody
The serum-concentration of at least about bispecific antibody of 1 μ g/ml is maintained in 21st day.
34. method as claimed in claim 33, the wherein subject maintain after giving the bispecific antibody in the 21st day
At least serum-concentration of the bispecific antibody of 5.3 μ g/ml.
35. method as claimed in claim 33, the wherein subject are about 7 days, about 21 days after giving the bispecific antibody
Or the serum-concentration of at least bispecific antibody of 1.7 μ g/mL is maintained in about 28 days.
Applications Claiming Priority (3)
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US201562260935P | 2015-11-30 | 2015-11-30 | |
US62/260935 | 2015-11-30 | ||
PCT/US2016/063865 WO2017095744A1 (en) | 2015-11-30 | 2016-11-28 | Method for preventing or treating nosocomial pneumonia |
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US (2) | US11066461B2 (en) |
EP (1) | EP3383884A4 (en) |
JP (2) | JP7110095B2 (en) |
KR (1) | KR20180088442A (en) |
CN (1) | CN108368149A (en) |
AU (1) | AU2016362202B2 (en) |
CA (1) | CA3005665A1 (en) |
HK (2) | HK1254854A1 (en) |
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HUE038509T2 (en) | 2011-06-10 | 2018-10-29 | Medimmune Ltd | Anti-pseudomonas psl binding molecules and uses thereof |
CA3161431A1 (en) * | 2011-11-07 | 2013-05-16 | Medimmune Limited | Combination therapies using anti-pseudomonas psl and pcrv binding molecules |
SG10201913100WA (en) | 2015-11-30 | 2020-03-30 | Medimmune Ltd | Method for preventing or treating nosocomial pneumonia |
CA3140075A1 (en) * | 2019-06-11 | 2020-12-17 | Regeneron Pharmaceuticals, Inc. | Anti-pcrv antibodies that bind pcrv, compositions comprising anti-pcrv antibodies, and methods of use thereof |
WO2023281120A1 (en) | 2021-07-09 | 2023-01-12 | Luxembourg Institute Of Health (Lih) | Dimeric protein complexes and uses thereof |
WO2024003103A1 (en) * | 2022-06-29 | 2024-01-04 | Astrazeneca Ab | Anti-pcrv and psl bispecific antibodies for treatment of bronchiectasis |
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WO2015171504A1 (en) * | 2014-05-05 | 2015-11-12 | Medimmune, Llc | Multi-specific anti-pseudomonas psl and pcrv binding molecules and uses thereof |
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US5892019A (en) | 1987-07-15 | 1999-04-06 | The United States Of America, As Represented By The Department Of Health And Human Services | Production of a single-gene-encoded immunoglobulin |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
DE69120146T2 (en) | 1990-01-12 | 1996-12-12 | Cell Genesys Inc | GENERATION OF XENOGENIC ANTIBODIES |
HUE038509T2 (en) | 2011-06-10 | 2018-10-29 | Medimmune Ltd | Anti-pseudomonas psl binding molecules and uses thereof |
CA3161431A1 (en) | 2011-11-07 | 2013-05-16 | Medimmune Limited | Combination therapies using anti-pseudomonas psl and pcrv binding molecules |
CN104995209A (en) * | 2012-11-06 | 2015-10-21 | 米迪缪尼有限公司 | Combination therapies using anti-pseudomonas psl and pcrv binding molecules |
AU2014265632B2 (en) | 2013-05-14 | 2019-09-19 | Medimmune, Llc | Synthetic oligosaccharide subunits of the psl exopolysaccharide of pseudomonas aeruginosa and uses thereof |
TWI719938B (en) | 2014-06-19 | 2021-03-01 | 美商麥迪紐有限責任公司 | Treatment of polybacterial infections |
SG10201913100WA (en) | 2015-11-30 | 2020-03-30 | Medimmune Ltd | Method for preventing or treating nosocomial pneumonia |
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IL259509A (en) | 2018-07-31 |
AU2016362202B2 (en) | 2020-02-27 |
JP2018535227A (en) | 2018-11-29 |
HK1257193A1 (en) | 2019-10-18 |
KR20180088442A (en) | 2018-08-03 |
HK1254854A1 (en) | 2019-07-26 |
AU2016362202A8 (en) | 2018-07-19 |
JP2022163050A (en) | 2022-10-25 |
US20180355026A1 (en) | 2018-12-13 |
SG10201913100WA (en) | 2020-03-30 |
CA3005665A1 (en) | 2017-06-08 |
US20220041695A1 (en) | 2022-02-10 |
US11066461B2 (en) | 2021-07-20 |
JP7110095B2 (en) | 2022-08-01 |
AU2016362202A1 (en) | 2018-07-05 |
EP3383884A4 (en) | 2019-07-31 |
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WO2017095744A1 (en) | 2017-06-08 |
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